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Guidelines 2011 libra.
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ORIGINS of ASTHMA
Attilio Boner
University of
Verona, Italy
attilio.boner@univr.it








Lung Development
Immunologic Maturation
Allergens
Exposure to Tobacco Smoke
Other adjuvant factors
Diet
Psychological factors
Conclusions
G
E
N
E
T
I
C
E
N
V
I
R
O
N
M
E
N
T
Lung development
Bronchial development
complete by the 16° week
True alveoli begin to
develop at 28 weeks and
increase in number, size
and complexity during the
first 3-4 years of life.
Dysanaptic growth and
Traking of lung function
TUCSON CHILDREN’S RESPIRATORY STUDY:
1980 TO PRESENT Taussig JACI 2003; 111:661
ALB
HYPOTHETICAL PEAK PREVALENCE BY AGE FOR THE 3
DIFFERENT WHEEZING PHENOTYPES.
LUNG FUNCTION ACCORDING TO
WHEEZING HISTORY AT 6 YEARS AT:
Early infancy
V
max
160 140 120 100 80 60 40 20 0
6 years of age
of FRC (ml/s)

-
V
-
*

-
-
*

-

-
1300 1200 -
1100 1000 -
early late persistent
transient
wheezers
Martinez NEJM 1995;332:133
of FRC (ml/s)
1400 -
p<0.05
never
max
900 800
*
*
-
p<0.05
never

-

-
early late persistent
transient
wheezers
TUCSON CHILDREN’S RESPIRATORY STUDY:
1980 TO PRESENT Taussig JACI 2003; 111:661
?
ALB
HYPOTHETICAL PEAK PREVALENCE BY AGE FOR THE 3
DIFFERENT WHEEZING PHENOTYPES.
WHEEZY BRONCHITIS IN CHILDHOOD.
A DISTINCT CLINICAL ENTITY WITH LIFELONG
SIGNIFICANCE? Edwards Chest 2003;124:18
Mean decline FEV1 (L)
between 1989 and 2001
 A cohort of
children
originally studied
in 1964 was
revaluated in 2002
(age 45-50) n=283
ALB
0
-10-20-30-40-50-60-70-80-
WHEEZY
ASTHMA BRONCHITISCONTROL
-0.59
-0.75 -0.75
(L)
(L)
(L)
p<0.01
Early life origins of chronic obstructive pulmonary
disease
Svanes Thorax 2010;65:14–20
European Community Respiratory Health Survey
participants aged 20–45 years randomly selected
from general populations.
Spirometry in 1991–3 (n=13,359)
and 9 years later (n=7,738).
•Maternal asthma,
•Paternal asthma,
•Childhood asthma,
•Maternal smoking and
•Childhood respiratory infections
defined as
‘‘childhood
disadvantage
factors’’.
Early life origins of chronic obstructive pulmonary
disease
Svanes Thorax 2010;65:14–20
OR for FEV1/FVC ≤ 70%
8 –
7 –
6 –
6.3
5 –
4 –
3 –
2 –
1 –
0
7.2
1.7
1
1.6
≥3
n°FACTORS IN MEN
1
≥3
n°FACTORS IN WOMEN
HYPOTHETICAL YEARLY PEAK PREVALENCE OF
WHEEZING ACCORDING TO PHENOTYPE IN
CHILDHOOD Martinez F., Pediatrics 2002; 109: 362
Transient early
wheezers
IgE-associated
wheeze/asthma
Wheezing
prevalence
Non-atopic
wheezers
0
alb
3
Age (years)
6
11
REDUCED LUNG FUNCTION BOTH BEFORE BRONCHIOLITIS AND AT 11 YRS
Turner Arch Dis Child 2002; 87: 417.
3
 253
cohort members
.
 VmaxFRC at 1 month
p=0.02
2
1
z score
of age
 Individuals with
bronchiolitis were
prospectively
identified
 At 11 years of age
lung function was
repeated
%VmaxFRC
0
-1
-2
-3
Confirmed
bronchiolitis
(n = 16)
Box and whisker plot for z scores
for % V’maxFRC at 1 month
Control
(n = 162)
TUCSON CHILDREN’S RESPIRATORY STUDY:
1980 TO PRESENT Taussig JACI 2003; 111:661
ALB
HYPOTHETICAL PEAK PREVALENCE BY AGE FOR THE 3
DIFFERENT WHEEZING PHENOTYPES.
Lung function according to wheezing history at 6 years at:
Martinez NEJM 1995; 332: 133
Early infancy
V
max
160 140 120 100 80 60 40 20 0
6 years of age
of FRC (ml/s)

-
V
-

-

-

-
max
of FRC (ml/s)
1400 1300 1200 -

-
1100 1000 -

-

-
late persistent
wheezers

-
900 -
never early
-
800
never
early
late persistent
wheezers
THE RELATIONSHIP BETWEEN INFANT AIRWAY FUNCTION,
CHILDHOOD AIRWAY RESPONSIVENESS, AND ASTHMA
Turner-Le Souef AJRCCM 2004; 169: 921

 VmaxFRC was assessed

at 1 month of age
 The presence of wheeze
up to 11 years of age
was prospectively
identified
 At 11 years of age,
airway responsiveness
(AR) to inhaled
histamine and atopy
were assessed
Z score VmaxFRC
p=0.02
2
1
0
-1
-2
NW
n=67
W 0-3 W 4-6
n=41
n=26
W 11
n=6
PW
n=17
Box and whisker plot showing median and

quartiles values for Z scores of VmaxFRC
at 1 month in groups defined by wheeze
at different ages.
REDUCED LUNG FUNCTION AT BIRTH AND THE
RISK OF ASTHMA AT 10 YEARS OF AGE
Haland , Carlsen N Engl J Med 2006; 355: 1682
30 –
20 –
% children with a history
of asthma at age 10 year
p=0.01
30 –
20 –
24.3%
10 –
0
16.2%
Above the median
% children with current
asthma at age 10 year
10 –
At-below the
median
tPTEF/tE at age 3 days
0
p=0.005
14.6%
7.5%
Above the median
At-below the
median
tPTEF/tE at age 3 days
ORIGINS of ASTHMA
 Lung Development
Attilio Boner
University of
Verona, Italy
Reduced lung development is a
premorbid predisposing factor for:
- Transient wheezing,
- Bronchiolitis,
- Persistent atopic wheezing,
ORIGINS of ASTHMA
Attilio Boner
University of
Verona, Italy
attilio.boner@univr.it








Lung Development
Immunologic Maturation
Allergens
Exposure to Tobacco Smoke
Other adjuvant factors
Diet
Psychological factors
Conclusions
G
E
N
E
T
I
C
E
N
V
I
R
O
N
M
E
N
T
MATERNO-PLACENTO-FETAL INTERACTIONS
Warner Arch Dis Child 2004;89:97
One of the explanations
for maintenance of a
successful pregnancy is
that both Th-2 (IL-4 and
IL-13) and T regulatory
(IL-10 and TGF-β)
cytokines are generated
by the conceptus to downregulate maternal Th-1
immune responses to
feto-paternal antigens
which might otherwise
lead to fetal rejection.
alb
SENSITIZATION DOES NOT DEVELOP IN UTERO
Bonnelykke
JACI 2008;121:646
 Inhalant and food
allergen-specific IgE
in cord blood and in
infant blood at 6
months of age and
in parental blood;
 Cord blood IgA was
measured to detect
maternal blood
contamination of
cord blood.
% of cord blood with (+) sIgE
15 –
10 –
5 –
0
14%
SENSITIZATION DOES NOT DEVELOP IN UTERO
Bonnelykke
 Inhalant and food
However,
allergen-specific
IgE
in cord
blood and in
corresponding
infant blood at 6
specific IgE was
months of age and
not blood;
found in
in parental
infant blood at 6
 Cord blood IgA was
months
of age.
measured
to detect
maternal blood
contamination of
cord blood.
JACI 2008;121:646
% of cord blood with (+) sIgE
15 –
10 –
5 –
0
14%
PRENATAL VERSUS POSTNATAL SENSITIZATION
TO ENVIRONMENTAL ALLERGENS IN A HIGH-RISK
BIRTH COHORT
Rowe JACI 2007;119:1164
 Prospectively
studied HDM
(house dust mite)
specific sIgE and
IgG4 and T-cell
immunity in a
cohort of 200
high-risk infants
0.35
Age (months)
Tracking antibody titers in individuals who
are HDM SPT-positive at age 24 months
SKIN BARRIER FUNCTION AND ALLERGIC RISK
Hudson Nature Genetics 2006; 38: 399
Skin barrier function and allergic risk. An intact epithelial barrier (a) prevents allergens from
reaching antigen presenting cells (APCs) in subepithelial tissues. Damage to this barrier (b)
allow allergens to penetrate into the subepidermal layer and interact with APCs, leading to
allergic sensitization and, secondarily, to allergic manifestations in the host.
FILLAGRIN LOSS-OF-FUNCTION MUTATIONS PREDISPOSE
TO PHENOTYPES INVOLVED IN THE ATOPIC MARCH
Marenholz
7 –
6 –
5 –
4 –
3 –
2 –
1 –
OR for
non atopic
eczema
JACI 2006; 118: 866
OR for
atopic
eczema
3.94
3.84
p=0.00065
p=0.0006
OR ratio for
concomitant
OR ratio for eczema and
concomitant
asthma
eczema and
allergic
6.21
rhinitis
4.79
p=0.00001
p=0.00001
0
IN CHILDREN WITH FILAGGRIN LOSS-OF-FUNCTION MUTATION
A pilot study of emollient therapy for the primary
prevention of atopic dermatitis.
Simpson EL, J Am Acad Dermatol. 2010;63:587-93.
22 neonates at high
risk for developing
AD
emollient therapy
from birth.
followed up mean
time of 547 days
50 –
40 –
30 –
20 –
10 –
0
% children who
developed AD
15%
A pilot study of emollient therapy for the primary
prevention of atopic dermatitis.
Simpson EL, J Am Acad Dermatol. 2010;63:587-93.
Chance of developing
AD in similar
high-risk
infants
22 neonates at high
risk for developing
AD
emollient therapy
from birth.
followed up mean
time of 547 days
50%
50 –
40 –
30 –
20 –
10 –
0
% children who
developed AD
15%
30%
Hoare C,
Health
Technol
Assess
2000;4:1-191.
A pilot study of emollient therapy for the primary
prevention of atopic dermatitis.
Simpson EL, J Am Acad Dermatol. 2010;63:587-93.
22 neonates at high
risk for developing
AD
emollient therapy
from birth.
followed up mean
time of 547 days
50 –
40 –
30 –
20 –
10 –
0
No side effect
% children who
developed AD
15%
Effects
on atopic
asthma
development?
ORIGINS of ASTHMA
Lung Development
 Immunologic Maturation
Attilio Boner
University of
Verona, Italy
The fetal life and the
newborn period are prone to
atopy.
Sensitization starts early but
postnataly.
Defective skin barrier fuction
predispose to allergy
development.
ORIGINS of ASTHMA
Attilio Boner
University of
Verona, Italy
attilio.boner@univr.it








Lung Development
Immunologic Maturation
Allergens
Exposure to Tobacco Smoke
Other adjuvant factors
Diet
Psychological factors
Conclusions
G
E
N
E
T
I
C
E
N
V
I
R
O
N
M
E
N
T
Early life risk factors for adult asthma: a birth cohort
study of subjects at risk Rhodes H.L JACI 2001; 108: 721
 Cohort study
 100 babies of
atopic parents
 Followed
- at 5 yrs,
- at 11 yrs,
- at 22 yrs
11109876543210
ODD ratio for adult asthma
10.7
(+) SPT for egg or milk in the first year
Early life risk factors for adult asthma: a birth cohort
study of subjects at risk Rhodes H.L JACI 2001; 108: 721
 Cohort study
 100 babies of
atopic parents
 Followed
- at 5 yrs,
- at 11 yrs,
- at 22 yrs
11109876543210
ODD ratio for adult asthma
10.7
(+) SPT for egg or milk in the first year
PERENNIAL ALLERGEN SENSITISATION EARLY IN LIFE AND
CHRONIC ASTHMA IN CHILDREN: A BIRTH COHORT STUDY
Illi Lancet 2006; 368: 763
 1314 children from
birth to 13 years of
age (MAS study)
 Allergen exposure
at age 6 months,
18 months, and
at 3, 4, and 5 yrs
 Lung function
at 7, 10, and 13 yrs
ALB
10 –
9 –
8
7
6
5
4
–
–
–
–
–
3 –
2 –
1 –
0
OR for BHR at school age
8.3
3.29
Early
Current
sensitization
sensitisation
(age <3)
to perennial allergen
THE CANADIAN CHILDHOOD ASTHMA PRIMARY
PREVENTION STUDY: OUTCOMES AT 7 YEARS OF AGE
Chan-Yeung JACI 2005; 116: 49
% ch. with pediatric
diagnosis of asthma
545 high-risk infants
with immediate FH
of asthma and
allergies
Intervention
(avoidance of house
dust) or control
groups
Outcomes at 7 years
30 –
20 –
p=0.006
23%
14.9%
10 –
OR =
0.44
0
Intervention
Controls
PREVENTION OF ALLERGIC DISEASE DURING
CHILDHOOD BY ALLERGEN AVOIDANCE: THE ISLE OF
WIGHT PREVENTION STUDY
Arshad JACI 2007;119:307
 Infants at higher risk
because of family
predisposition.
1 –
OR in the prophylactic group
at age 8 years
 Randomized to
prophylactic (n=58) and
control (n=62) groups.
 Prophylactic group:
breast-fed or
extensively hydrolyzed
formula, acaricide and
mattress covers.
 Development of allergic
disease at age 1,2,4 and
8 years.
0,5 –
0.24
p=0.005
0
asthma
0.23
p=0.005
Atopic
dermatitis
0.14
0.13
p=0.0003 p<0.005
Allergic
rhinitis
atopy
EARLY LIFE ENVIROMENTAL CONTROL: EFFECT ON
SYMPTOMS, SENSITIZATION AND LUNG FUNCTION
AT AGE 3 YEARS Woodcock AJRCCM 2004;170:433
•Manchester
cohort
•128 active group
•111 control group
•Allergen level,
symptoms,
sensitization and
lung function at 3
years of age
ALB
Ln VmaxFRC GM & 95% CI
1.0 –
at age 4 weeks
0.8 –
0.6 –
0.4 –
0.2 –
0.0
*
p=0.49
*
EARLY LIFE ENVIROMENTAL CONTROL: EFFECT ON
SYMPTOMS, SENSITIZATION AND LUNG FUNCTION
AT AGE 3 YEARS Woodcock AJRCCM 2004;170:433
•Manchester
cohort
•128 active group
•111 control group
•Allergen level,
symptoms,
sensitization and
lung function at 3
years of age
ALB
0.4 –
Ln sRaw GM & 95% CI at
age 3 years
0.3 –
0.2 –
0.1 –
0.0 –
-.1
*
p=0.003
*
EARLY LIFE ENVIROMENTAL CONTROL: EFFECT ON
SYMPTOMS, SENSITIZATION AND LUNG FUNCTION
AT AGE 3 YEARS Woodcock AJRCCM 2004;170:433
• Manchester
0.4
cohort
This may be an
• 128 active group
important factor 0.3
• 111 control group
in relation to the 0.2
• Allergen level,
traking
effect of 0.1
symptoms,
lung function
sensitization
and
0.0
lung function at
3 years of age
-.1
–
Ln sRaw GM & 95% CI at
age 3 years
–
–
–
–
*
p=0.003
*
A LONGITUDINAL, POPULATION-BASED, COHORT
STUDY OF CHILDHOOD ASTHMA FOLLOWED TO
ADULTHOOD.Sears NEJM 2003;349:1414
 1139 newborn (April
1972-March 1973);
 Assessed at 3 yrs,
every 2 yrs up to 15
yrs than at 18, 21, and
26 yrs of age;
 Questionnaire;
 Lung function;
 SPT, sIgE;
 Methacholine ch.
100 –
90 –
% SUBJECTS AT 26 YEARS
80 –
70 –
60 –
50 –
40 –
30 –
72.6
20 –
51.4
10 –
26.9
0
WHEEZING
ONCE
>ONCE
CURRENTLY
A LONGITUDINAL, POPULATION-BASED, COHORT
STUDY OF CHILDHOOD ASTHMA FOLLOWED TO
ADULTHOOD.Sears NEJM 2003;349:1414
 1139 newborn (April
1972-March 1973);
 Assessed at 3 yrs,
every 2 yrs up to 15
yrs than at 18, 21, and
26 yrs of age;
 Questionnaire;
 Lung function;
 SPT, sIgE;
 Methacholine ch.
% SUBJECTS AT 26 YEARS
30 –
20 –
10 –
26.9
12.4% HAD
REMISSION
FOLLOWED BY
RELAPSE BY
AGE 26
14.5
0
WHEEZING
CURRENTLY
PERSISTENT
A LONGITUDINAL, POPULATION-BASED, COHORT
STUDY OF CHILDHOOD ASTHMA FOLLOWED TO
ADULTHOOD.Sears NEJM 2003;349:1414
5 4 3 –
2 –
1 –
0
OR FOR WHEEZING AT AGE
26 YEARS
p<0.001 for trend
3.38
FOR
PERSISTANCE
4.17
FOR
RELAPSE
(+) SPT FOR MITES AT AGE 13 YEARS
ORIGINS of ASTHMA
Lung Development
 Immunologic Maturation
 Allergens
•Early sensitization to
Attilio Boner
University of
Verona, Italy
allergens is a risk factor for
more severe asthma and
reduced lung function,
•Sensitization may occur
through the skin,
•Sesitization can occur also
later in life and is always a
risk factor for asthma
ORIGINS of ASTHMA
Attilio Boner
University of
Verona, Italy
attilio.boner@univr.it








Lung Development
Immunologic Maturation
Allergens
Exposure to Tobacco Smoke
Other adjuvant factors
Diet
Psychological factors
Conclusions
G
E
N
E
T
I
C
E
N
V
I
R
O
N
M
E
N
T
THE EFFECT OF MATERNAL SMOKING DURING
PREGNANCY ON EARLY INFANT LUNG FUNCTION
Hanrahan Am. Rev. Respir. Dis. 1992; 145: 1129
80 healthy infants
tested shortly
after birth
(mean, 4.2+/-1.9 wk)
Urine cotinine
Expiratory flowvolume curves
200 –
Flow at functional
residual capacity (ml/s)
p= 0.0007
150 –
150.4
100 –
50 –
0
74.3
YES
NO
SMOKING MOTHER
MATERNAL AND GRANDMATERNAL SMOKING PATTERNS
ARE ASSOCIATED WITH EARLY CHILDHOOD ASTHMA
Li YF Chest 2005; 127: 1232
OR for asthma in the first 5 years of life
 338 children
with asthma
diagnosed
in the first 5
years of life
 570 control
subjects
2.6
3 –
2 –
1.3
1.8
1 –
0
Smoking
mother
only
Grandmaternal
Grandmaternal
only smoking during and maternal
the mother’s fetal
smoking
period
THE ADULT INCIDENCE OF ASTHMA AND RESPIRATORY
SYMPTOMS BY PASSIVE SMOKING IN UTERO OR IN
CHILDHOOD
Skorge AJRCCM 2005; 172: 61
OR ratio for adult
onset asthma
 Between 1985 and
1996/1997 an 11-year
community cohort
study on the
incidence of asthma
3 –
2 –
3
1 –
 3.786 subjects
0
Smoking mother
THE ADULT INCIDENCE OF ASTHMA AND RESPIRATORY
SYMPTOMS BY PASSIVE SMOKING IN UTERO OR IN
CHILDHOOD
Skorge AJRCCM 2005; 172: 61
The adjusted
attributable
fractions1985
of the
 Between
and
adult
incidence
of
1996/1997
an 11-year
asthma were
community
cohort
study oncaused
the
17.3%
by
incidence smoking
of asthma
maternal
and 9.3% caused by
 3.786 subjects
smoking by other
household members.
OR ratio for adult
onset asthma
3 –
2 –
3
1 –
0
Smoking mother
REGULAR SMOKING AND ASTHMA INCIDENCE IN
ADOLESCENTS Gilliland AJRCCM 2006; 174: 1094
RR FOR NEW ONSET
OF ASTHMA
 2,609 children with no
lifetime history of
asthma or wheezing
 Followed annually
in schools
 Regular smoking was
defined as smoking 300
cigarettes in the year
 New cases of physiciandiagnosed asthma
4 –
3 –
2 –
3.9
1 –
0
In children smoking
>300 cigarettes/year
REGULAR SMOKING AND ASTHMA INCIDENCE IN
ADOLESCENTS Gilliland AJRCCM 2006; 174: 1094
10-
 2,609 children with no
lifetime history of
asthma or wheezing
 Followed annually
in schools
 Regular smoking was
defined as smoking 300
cigarettes in the year
 New cases of physiciandiagnosed asthma
8 –
6 –
4 –
RR FOR NEW ONSET
OF ASTHMA
8.8
2 –
0
In children smoking
>300 cigarettes/year and
exposed to maternal smoking
during gestation
ORIGINS of ASTHMA
 Lung Development
 Immunologic Maturation
 Allergens

Exposure to Tobacco Smoke
Smoking should always be
avoided by anyone.
Attilio Boner
University of
Verona, Italy
ORIGINS of ASTHMA
Attilio Boner
University of
Verona, Italy
attilio.boner@univr.it








Lung Development
Immunologic Maturation
Allergens
Exposure to Tobacco Smoke
Other adjuvant factors
Diet
Psychological factors
Conclusions
G
E
N
E
T
I
C
E
N
V
I
R
O
N
M
E
N
T
SYNTHETIC BEDDING AND WHEEZE IN
CHILDHOOD. Ponsonby Epidemilogy 2003;14:37
OR for wheezing at 7 yrs
7 –
 Bedding type at
1mo
 Wheeze at 7 yrs
(n=6,378 ch)
6 –
5 –
5.2
4 –
3 –
2 –
2.5
+
1 –
0
synthetic
pillow
+synthetic
quilt
A prospective association between synthetic cocoon
use in infancy and childhooh asthma.
Trevillian Paed Perin Epidem 2004:18:281
• Sleeping
environment
of 863 infants
evaluated at
1 month of life
• Follow-up:
7 years
5 4 3 –
2 –
1 –
0
OR FOR
4.33
RECENT
WHEEZE
AT AGE
7 YEARS
3.35
NIGHT
WHEEZE
AT AGE
7 YEARS
IN CH. SLEEPING IN A SYNTHETIC
COCOON AT 1 MONTH OF AGE
FREQUENT USE OF CHEMICAL HOUSEHOLD PRODUCTS
IS ASSOCIATED WITH PERSISTENT WHEEZING IN
PRE-SCHOOL AGE CHILDREN. Sherriff Thorax 2005; 60: 45
OR FOR PERSISTENT WHEEZE
 Population based Avon
Longitudinal Study of Parents
and Children.
 Frequency of use of 11
chemical based domestic
products determined from
questionnaires completed by
women during pregnancy.
 A total chemical burden
(TCB) score was derived.
2.5 –
2.0 –
1.5 –
2.3
1.0 –
0.5 –
P=0.012
0.0
In children whose mothers had high
TCB scores (>90th centile) than
children whose mothers had a low
TCB score (<10th centile).
IS IT TRAFFIC TYPE, VOLUME, OR DISTANCE? WHEEZING
IN INFANTS LIVING NEAR TRUCK AND BUS TRAFFIC
Ryan JACI 2005; 116: 279
 The relationship
between types of
traffic, traffic
volume, and distance
and wheezing among
infants less than
1 year of age
3 –
2 –
1 –
OR for wheezing
in the 1°yr
2.5
0
In infants living very near (< 100 m)
to stop-and-go bus and truck traffic
ORIGINS of ASTHMA




Lung Development
Immunologic Maturation
Allergens
Exposure to Tobacco Smoke
 Other adjuvant factors
Attilio Boner
University of
Verona, Italy
Early contact with:
-Synthetic materials
-Detergents spray
-Pollution
-………
are important adjuvant
factors.
ORIGINS of ASTHMA
Attilio Boner
University of
Verona, Italy
attilio.boner@univr.it








Lung Development
Immunologic Maturation
Allergens
Exposure to Tobacco Smoke
Other adjuvant factors
Diet
Psychological factors
Conclusions
G
E
N
E
T
I
C
E
N
V
I
R
O
N
M
E
N
T
1) MATERNAL INTAKE OF VITAMIN D DURING
PREGNANCY AND RISK OF RECURRENT WHEEZE IN
CHILDREN AT 3 Y OF AGE
Camargo Am J Clin Nutr 2007; 85: 788
2) MATERNAL VITAMIN D INTAKE DURING
PREGNANCY AND EARLY CHILDHOOD WHEEZING
Devereux Am J Clin Nutr 2007; 85: 853
“ using data from the two birth cohorts with maternal
vitamin D assessment, we estimate that the
population attributable risk for asthma incidence
caused by vitamin D deficiency in pregancy is about
40% of all cases.” Weiss JACI 2007;120:1031
LOW MATERNAL VITAMIN E INTAKE DURING PREGNANCY
IS ASSOCIATED WITH ASTHMA IN 5-YEARS-OLD
CHILDREN Devereux AJRCCM 2006; 174: 499
OR FOR WHEEZE WITHOUT A COLD IN THE LAST 12 MO
 1,861 children
born to women 1recruited during
pregnancy and
followed up
at 5 yr;
 Maternal
nutrient status
by a food
frequency
questionnaire
and plasma
levels.
1
p = 0.02 for trend
0.50
0.56
0.53
0.22
1
2
QUINTILES OF
VIT E
3
4
5
INTAKE IN THE MOTHER
LOW MATERNAL VITAMIN E INTAKE DURING PREGNANCY
IS ASSOCIATED WITH ASTHMA IN 5-YEARS-OLD
CHILDREN Devereux AJRCCM 2006; 174: 499
OR FOR EVER ASTHMA
 1,861 children
born to women 1recruited during
pregnancy and
followed up
at 5 yr;
 Maternal
nutrient status
by a food
frequency
questionnaire
and plasma
levels.
1
p = 0.04 for trend
0.55
1
2
QUINTILES
0.59
3
OF ZINC
0.44
4
INTAKE
0.51
5
MEDITERRANEAN DIET IN PREGNANCY IS PROTECTIVE
FOR WHEEZE AND ATOPY IN CHILDHOOD
Chatzi Thorax 2008; 63: 507
 Women presenting
for antenatal care
at all general
practices in
Menorca.
 460 children were
included in the
analysis after
6.5 years of
follow-up.
 Food frequency
questionnaires.
1.0 –
With high Mediterranean Diet
Score during pregnancy OR for
0.5 –
0.0
0.55
0.22
PERSISTENT
WHEEZE
0.30
ATOPIC
WHEEZE
at age 6.5 years
ATOPY
PROTECTIVE EFFECT OF FRUITS, VEGETABLES AND THE
MEDITERRANEAN DIET ON ASTHMA AND ALLERGIES
AMONG CHILDREN IN CRETE Chatzi Thorax 2007;62:677
 Cross-sectional survey.
 690 children aged 7-18
years in rural Crete.
 Questionaire on
respiratory and allergic
symptoms and a 58-item
food frequency
qestionaire.
 SPTs.
1.0 –
0.5 –
0
OR for WHEEZING EVER
p=0.001 for trend
0.26
< 1/DAY
0.19
> 1/DAY
GRAPES
Maternal fish intake during pregnancy and atopy and
asthma in infancy. Romieu Clin Exp All 2007;37:518
In children of mothers with fish
intake during pregnancy OR for
 A cohort of
women (n=462)
enrolled during
pregnancy
1 –
0.73
 Offspring
followed up
to 6 years
0
eczema
at 1 yr
0.68
(+) SPT to
HDM at age
6 yrs
0.55
Asthma at
age 6 yrs
Low physical fitness in childhood is associated with
the development of asthma in young adulthood: the
Odense school child study. Rasmussen ERJ 2000;16:866
• 757 healthy
schoolchildren
(mean age 9.7 yrs)
• Follow-up 10.5 yrs
• Progressive
exercise test
(maximal workload)
on a bicycle
ergometer
% ch who developed asthma in the
10 yrs follow-up
10 –
8 –
6 –
4 –
2 –
0
6.7%
Low physical fitness in childhood is associated with
the development of asthma in young adulthood: the
Odense school child study. Rasmussen ERJ 2000;16:866
• 757 healthy
schoolchildren
(mean age 9.7 yrs)
• Follow-up 10.5 yrs
• Progressive
exercise test
(maximal workload)
on a bicycle
ergometer
% ch who developed asthma in the
10 yrs follow-up
10 –
8 –
6 –
4 –
2 –
0
6.7%
These children had a
significant (p=0.02)
reduced mean physical
fitness at the time of
enrolment into the
study.
ASSOCIATIONS BETWEEN POSTNATAL WEIGHT GAIN, CHANGE
IN POSTNATAL PULMONARY FUNCTION, FORMULA FEEDING AND
EARLY ASTHMA. Turner Thorax 2008; 63: 234
P=0.003
 154 infants
FOR TREND
 Weight, length and
maximal flow at
functional residual
capacity (V’maxFRC)
at ages 1 and 12 months.
 Age at introduction
formula feeds from
questionnaires.
of
ORIGINS of ASTHMA




Lung Development
Immunologic Maturation
Allergens
Exposure to Tobacco Smoke
 Diet and life-style
Attilio Boner
University of
Verona, Italy
“Early life (conception to 2
years) dietary exposure
might be particularly
important in the development
of childhood asthma.”
ORIGINS of ASTHMA
Attilio Boner
University of
Verona, Italy
attilio.boner@univr.it








Lung Development
Immunologic Maturation
Allergens
Exposure to Tobacco Smoke
Other adjuvant factors
Diet and life-style
Psychological factors
Conclusions
G
E
N
E
T
I
C
E
N
V
I
R
O
N
M
E
N
T
Mothers’ anxiety during pregnancy is associated with
asthma in their children Cookson JACI 2009; 123:847
OR FOR CURRENT ASTHMA
AT 7½ YRS.
 Avon Longitudinal
Study of Parents
and Children
(5810 children).
 Anxiety assessed at
18 and 32 weeks of
gestation.
 Asthma was defined
at age 7½ years.
P<0.001 FOR TREND
2.0 1.5 1.0 –
1
1.33 1.46
1.68
0.5 –
0
1st
2nd
3rd
4th
MATERNAL ANXIETY QUARTILE AT 32 WK
PARENTAL STRESS AS A PREDICTOR OF
WHEEZING IN INFANCY: A PROSPECTIVE
BIRTH-COHORT STUDY
Wright Am J Respir Crit Care Med 2002; 165: 358
RR of wheezing during
the first 14 mo.
influence of caregiver
stress on wheeze in
infancy
genetically
1.6
1 -
predisposed birthcohort (n=496)
Greater level of
stress in caregivers
CHRONIC CAREGIVER STRESS AND IGE EXPRESSION,
ALLERGEN-INDUCED PROLIFERATION, AND CYTOKINE
PROFILES IN A BIRTH COHORT PREDISPOSED TO ATOPY
Wright
 Caregiver stress
evaluated by
Perceived Stress
Scale in the first
2 yrs
 Total IgE and
proliferative
response to HDM
JACI 2004; 113: 1051
3 2 –
OR in children (6-18 mo) for
IgE > 100 vs ≤ 100 UI/ml
2.03
1 –
0
With higher caregiver stress
STRESSFUL LIFE EVENTS AND ASTHMA IN
ADOLESCENTS Turyk Pediatr Allergy Immunol 2008;19:255
2.0 –
 Self-reported asthma.
 2026 (seventh to ninth
grade: 12-15 yrs)
students from 34
Chicago schools.
 15 different life
events were evaluated
0R
FOR ASTHMA
1.92
1.5 –
1.0 –
1.44
0.5 –
0
2-3
>3
N° OF STRESSFUL
EVENTS
A TWIN STUDY OF POST-TRAUMATIC STRESS
DISORDER SYMPTOMS AND ASTHMA
Goodwin AJRCCM 2007;176:983
3 –
Kim Phuc
 Association
between posttraumatic stress
disorder (PTSD)
symptoms and
asthma.
 Data from twins in
the Vietnam Era
Twin Registry.
2 –
1 –
0
Likelihood ratio of developing
asthma
2.3
P<0.001
In veterans in the highest
quartile of PTSD compared to
those in the lowest
ORIGINS of ASTHMA





Lung Development
Immunologic Maturation
Allergens
Exposure to Tobacco Smoke
Diet
 Psychological factors
Attilio Boner
University of
Verona, Italy
Psychological factors may
predispose to wheeze and atopy
through neuro-immunological
mechanisms.
ORIGINS of ASTHMA
Attilio Boner
University of
Verona, Italy
attilio.boner@univr.it








Lung Development
Immunologic Maturation
Allergens
Exposure to Tobacco Smoke
Other adjuvant factors
Diet and life-style
Psychological factors
Conclusions
G
E
N
E
T
I
C
E
N
V
I
R
O
N
M
E
N
T
Fetal and early postnatal life roots of asthma.
Boner AL J Matern Fetal Neonatal Med. 2010;23 Suppl 3:80-3.
The origins of asthma might be traced back to events occurring
during fetal life.
Reduced lung development has been shown to be a risk factor
both for viral induced wheeze and allergic asthma.
The evidence for a causal relationship between exposure to
environmental tobacco smoke, chemical domestic products for
cleaning, outdoor pollutants, and reduction in lung function is quite
strong.
Reduced maternal intake of vitamin E, vitamin D, and zinc, is
associated with increased wheezing outcomes in children.
The risk of developing allergic asthma is increased if the child is
exposed in the first months of life to synthetic bedding and is
enhanced by allergen exposure and by an inadequate barrier
function of the skin.
STRATEGIES FOR PREVENTING WHEEZING AND
ASTHMA IN SMALL CHILDREN. Wickman Allergy 2003;58:742
Birth cohort 4089 ch
Families who lived
according the Swedish
primary prevention
guidelines:
1.breastfeeding
2.no tabacco smoke
3.good ventilation &
reduced dampness
*NO=exposed to
≥2 risk factors
RECURRENT WHEEZING AT 2 YRS
302010-
0
12.6%
YES
24.1%
NO*
living according to guidelines
STRATEGIES FOR PREVENTING WHEEZING AND
ASTHMA IN SMALL CHILDREN. Wickman Allergy 2003;58:742
Birth cohort 4089 ch
RECURRENT WHEEZING AT 2 YRS
30Families who lived
CAN ASTHMA
AND
according the Swedish
ALLERGY BE PREVENTED
primary prevention
guidelines:
20- LIFE?
IN REAL
Carlsen Allergy 2003;58:730
24.1%
1.breastfeeding
2.no tabacco“The
smoke
present 10study shows that
3.good ventilation
&
prevention
of asthma and allergy
reduced dampness
may be very
0 effective.”
12.6%
*NO=exposed to
≥2 risk factors
YES
NO*
living according to guidelines
STRATEGIES FOR PREVENTING WHEEZING AND
ASTHMA IN SMALL CHILDREN. Wickman Allergy 2003;58:742
Birth cohort 4089 ch
ASTHMA AT AGE 2
Families who lived
20according the Swedish
primary prevention
guidelines:IN CHILDREN WITH HEREDITY TO ASTHMA,
LIVING ACCORDING TO THE GUIDELINES
GAVE A THREEFOLD
101.breastfeeding
DECREASE IN ASTHMA AND IN CHILDREN
2.no tabacco
smoke
WITH
NO HEREDITY A TWOFOLD REDUCTION
3.good ventilation & Carlsen Allergy 2003;58:730
reduced dampness
0
17.9%
6.8%
*NO=exposed to
≥2 risk factors
YES
NO*
THE BRITISH 1958 COHORT.
A MESSAGE FOR OBSTETRICIANS AND PEDIATRICIANS.
Boner AJRCCM 2007; 175: 298
“All effort should be made to prevent intrauterine
insults that may perturb lung development:
1) No maternal smoking during pregnancy,
2)No maternal undernutrition,
3)No maternal hypertension which may cause placental
hypoxia,
4)No oligodramnios,
In children may be of help:
1) Reduction of allergen exposure in early life,
2)Regular consumption of fresh fruit and vegetables,
3)Reduction of indoor and outdoor pollution,
4)Regular physical activity.